Domestic cats are subject to infection by several retroviruses, including feline leukemia virus (FeLV), feline sarcoma virus (FeSV), endogenous type C oncoronavirus (RD-114), and feline syncytia-forming virus (FeSFV). Of these, FeLV is the most significant pathogen, causing diverse symptoms including lymphoreticular and myeloid neoplasms, anemias, immune-mediated disorders, and an immunodeficiency syndrome that is similar to human acquired immune deficiency syndrome (AIDS). Recently, a particular replication-defective FeLV mutant, designated FeLV-AIDS, has been more particularly associated with immunosuppressive properties.
The discovery of feline T-lymphotropic lentivirus (now designated as feline immunodeficiency virus, FIV) was first reported in Pedersen et al. (1987). Characteristics of FIV have been reported in Yamamoto et al. (1988a); Yamamoto et al. (1988b); and Ackley et al. (1990). Seroepidemiologic data have shown that infection by FIV is indigenous to domestic and wild felines throughout the world. A wide variety of symptoms are associated with infection by FIV, including abortion, alopecia, anemia, conjunctivitis, chronic rhinitis, enteritis, gingivitis, hematochezia, neurologic abnormalities, periodontitis, and seborrheic dermatitis. The immunologic hallmark of domestic cats infected with FIV is a chronic and progressive depletion of feline CD4+ peripheral blood lymphocytes, a reduction in the CD4:CD8 cell ratio and, in some cases, an increase in CD8-bearing lymphocytes. Based on molecular, biochemical and immunopathologic characteristics, FIV infection of cats is now considered to be a better feline AIDS model than FeLV-FAIDS.
Cloning and sequence analysis of FIV has been reported in Olmsted et al. (1989a); Olmsted et al. (1989b); and Talbott et al. (1989). Hosie and Jarrett (1990) described the serological response of cats infected with FIV. FIV virus subtypes can be classified according to immunotype based on the level of cross-neutralizing antibodies elicited by each strain (Murphy and Kingsbury, 1990). Recently, viruses have been classified into subtypes according to genotype based on nucleotide sequence homology. Although HIV and FIV subtyping is based on genotype (Sodora et al., 1994; Rigby et al., 1993; and Louwagie et al., 1993), little is known about the correlation between the genotype and immunotype of subtypes. FIV viral isolates have been classified into four FIV subtypes: A, B, C and D. (Kakinuma et al., 1995). Infectious isolates and infectious molecular clones have been described for all FIV subtypes except for subtype C (Sodora et al., 1994). Subtype C FIV has originally been identified from cellular DNA of cats from Canada (Sodora et al., 1994; Rigby et al., 1993; Kakinuma et al., 1995). FIV strains identified in the art include (subtype of the strain is shown in parenthesis) Petaluma (A), Dixon (A), UK8 (A), Dutch113 (A), Dutch19K (A), UK2 (A), SwissZ2 (A), Sendai-1 (A), USCAzepy01A (A), USCAhnky11A (A), USCAtt-10A (A), USCAlemy01 (A), USCAsam-01A (A), PPR (A), FranceWo, Netherlands, Bangston (A/B), Aomori-1 (B), Aomori-2 (B), USILbrny03B (B), TM2 (B), Sendai-2 (B), USCKlgri02B (B), Yokohama (B), USMAsboy03B (B), USTXmtex03B (B), USMCglwd03B (B), CABCpbar03C (C), CABCpbar07C (C), CABCpady02C (C), Shizuoka (D), and Fukuoka (D).
Although major strides have been made with antiviral drug therapy, the development of an effective vaccine against HIV-1 is still considered central to the control of the AIDS epidemic (Calarota et al., 2003). Multiple HIV vaccine designs using different HIV-1 strains are currently in various phases of clinical trials (Calarota et al., 2003; Cohen, 2003; IAVI Report. Ongoing trials of preventive HIV vaccines (last updated: Dec. 14, 2004). IAVI Report Online Special Features: www.iavireport.org/specials/OngoingTrialsofPreventiveHIVVaccines.pdf). Even in light of these clinical trials, it is still unclear what HIV-1 epitopes and immune mechanisms are essential for vaccine protection (Calarota et al., 2003; McMichael et al., 2003). Similar issues were faced during the development of an FIV vaccine for domestic cats (Uhl et al., 2002). As a means to broaden FIV vaccine efficacy, a dual-subtype vaccine was developed using FIV strains from long-term nonprogressor cats (Uhl et al., 2002; Yamamoto et al., 2002). This vaccine demonstrated moderate to significant protection of cats against both homologous and heterologous FIV challenges (Uhl et al., 2002; Yamamoto et al., 2002, Pu et al., 2001; Pu et al., 2005). Furthermore, this vaccine induced not only broad neutralizing antibodies (Pu et al., 2001) but antibodies cross-reactive to HIV-1 proteins, especially to HIV-1 core protein (p24) and group-specific antigens (Gag) (Pu et al., 2002). The FIV epitopes responsible for providing the dual-subtype vaccine protection have yet to be determined.
Gag and other antigens conserved among viruses from the same subfamily frequently induce antibodies that cross-react with other subfamily members (Pu et al., 2002; Matsuo et al., 1992; Nath et al., 2001; Zvelebil et al., 1988; Murphy, 1996). Some cross-reactive antigens have been used as immunogens for vaccine against viruses from the same subfamily (Henderson et al., 2004; Yazbak et al., 2002). Classic examples of such vaccines are the use of vaccinia virus vaccines for smallpox in humans and human measles vaccines for canine distemper in puppies (Henderson et al., 2004; Yazbak et al., 2002). Consequently, protective vaccines based on cross-reactive antigens have been shown to provide broad immunity, and may be useful against viruses that are currently evolving in a new host, such as HIV infection of humans.
Although cross-protection against HIV-1 with prior HIV-2 infection has been reported in multiple retrospective studies (Travers et al., 1995; Greenberg et al., 1996), controversy still exists with multiple studies reporting no protection (Norrgren et al., 1999; Schim van der Loeff et al., 2001). Even though amino acid (aa) sequences of the structural gene products exhibit only limited identity (<60%) between HIV-1 and HIV-2 (Guyader et al., 1987), some of the cross-reactive epitopes between these two major HIV groups have been reported to induce cross-neutralizing antibodies and cross-reactive cytotoxic T lymphocyte (CTL) activities (Robert-Guroff et al., 1992; Bottiger et al., 1990; Nixon et al., 1990; Rowland-Jones et al., 1995). Moreover, poxvirus-vectored recombinant HIV-1 vaccine priming followed by HIV-1 protein boost, conferred cross-protection against HIV-2 challenge in macaques (Abimiku et al., 1995). However, cross-reactive antigen-induced protective immunity has not been reported against distinct heterologous-species viruses (HIV-1 and FIV).